David B. Mansur and Jeff M. Michalski
Neuroblastoma is an enigmatic malignant neoplasm. In its early stages it can be readily cured with surgery or, in some circumstances, can even spontaneously regress or mature to a benign ganglioneuroma. In the more common advanced stages, the disease is often fatal. The unique biology of neuroblastoma has attracted the interest of many prominent scientists and is one of the first malignancies in which molecular biologic assays have influenced treatment and prognosis.
EPIDEMIOLOGY
After brain tumors and leukemia, neuroblastoma is the third-most-common malignancy diagnosed in children, with an annual incidence of 9 new cases per 1 million children in the United States. It is the most common cancer diagnosed before the age of 12 months, accounting for almost half of all cancers in infants. The median age at diagnosis is 2 years. The relatively good prognosis of infants diagnosed with early-stage neuroblastoma prompted the initiation of infant-screening studies.1
Screening of infants for neuroblastoma has been studied systematically in large clinical trials conducted in Japan, North America, and Europe.2–5 Excretion of catecholamine metabolites in the urine of children with neuroblastoma has served as the basis of these screening tests. Urine samples were collected and dried on filter paper and returned to screening centers to be tested qualitatively for vanillylmandelic acid (VMA) levels or quantitatively for VMA and homovanillic acid (HVA) measured by high-performance liquid chromatography and normalized to urinary creatinine levels. Children with elevated levels of these metabolites subsequently were referred for further diagnostic evaluation. The incidences of the diagnosis and death rates from neuroblastoma in the screened populations were compared to control populations in the same country or continent. The study populations generally were chosen because of access to an existing screening infrastructure that could readily be adapted to neuroblastoma. The Japanese study screened children at 6 months of age. The Quebec study screened children at 3 weeks and 6 months of age. The German study tested children at their first year’s birthday.
The results and conclusions of these three large screening trials on three continents are remarkably similar. In Japan, 1,142,519 children were screened using a qualitative test, and another 550,331 were screened with the quantitative test; they all were compared to 713,025 children in a control population. The incidence rates per 100,000 were 1.12 in the control group compared to 5.69 in the qualitative group and 17.81 in the quantitative group. Despite this increased incidence in the screened group, the neuroblastoma mortality rates were unchanged by the screening.5 In Germany, 1,475,773 children were screened between 1994 and 1999. Screening detected neuroblastoma in 149 children, 3 of whom died. Despite the screening at 12 months, another 55 children subsequently developed neuroblastoma, 14 of whom died. Compared to the control group, the incidence of stage 4 neuroblastoma was similar. The death rate from neuroblastoma was unaffected by the screening.3 In Quebec, a total of 425,838 children were enrolled in the neuroblastoma screening trial (89% of births during a 5-year study period from 1989 to 1994). The standardized incidence ratios of neuroblastoma death in the Quebec cohort were nearly identical to those in control groups in Ontario, Minnesota, Florida, and the Greater Delaware Valley.4 In summary, each of these trials demonstrates that screening does not affect the mortality rate of neuroblastoma. Furthermore, the overdiagnosis of clinically insignificant disease may lead to significant financial, emotional, and physical burdens on the children and their families. This tumor has a high frequency of spontaneous regression in infancy. The mass screening programs have led to the diagnosis of biologically favorable and clinically insignificant tumors.6,7
NATURAL HISTORY
Neuroblastoma, along with ganglioneuroma and ganglioneuroblastoma, may arise from any site in the sympathetic nervous system. The most common sites of origin are the adrenal medulla (30% to 40%) and paraspinal ganglia in the abdomen or pelvis (25%). Thoracic (15%) and head and neck primary tumors (5%) are slightly more common in infants than in older children. More than 70% of patients have metastatic disease at presentation. The most frequent metastatic sites are lymph nodes, bone, bone marrow, skin (or subcutaneous tissues), and liver.8 The lung and central nervous system are rare sites of involvement.
Neuroblastoma has the highest spontaneous remission rate of any human neoplasm, usually by maturation to ganglioneuroma.9 Microscopic neuroblastomas have been found in the autopsy material of the adrenal glands of young infants at >40 times the expected rate. It has been suggested that most potential neuroblastomas are never clinically manifested, because of spontaneous regression.10 Despite these peculiarities, clinically obvious neuroblastoma is frequently a progressive and relentless disease.
CLINICAL PRESENTATION
Pain is the most common presenting symptom. This frequently is caused by bone, liver, or bone marrow metastases or local visceral invasion by the primary tumor. Other constitutional symptoms may include weight loss, anorexia, malaise, and fever. Respiratory distress may accompany massive hepatomegaly, especially in infants with stage IV-S disease.8 Horner’s syndrome can accompany a primary tumor originating in the neck. Spinal cord compression with paralysis of the lower extremities can accompany the so-called dumbbell-shaped tumor that extends from its origin along the sympathetic ganglia through the adjacent neural foramina. Orbital metastases are not uncommon and can cause proptosis and ecchymosis. Skin metastases may have a bluish tinge, giving the classic “blueberry muffin” sign. When pressed, the release of catecholamine into the tissue causes transient blanching of the adjacent skin. An unusual presentation of localized neuroblastoma is the opsoclonus–myoclonus syndrome, manifested by truncal ataxia and cerebellar encephalopathy. This syndrome typically indicates a favorable prognosis from the tumor, but patients may have persistent neurologic sequelae after successful tumor therapy.11,12
DIAGNOSTIC WORKUP
As in the case of any suspected malignant neoplasm in children, the diagnosis of neuroblastoma must be established by pathologic evaluation. Tumor tissue may be obtained from the suspected primary tumor site or from involved lymph nodes by excision (if the tumor is resectable) or incisional biopsy. Bone marrow aspirate and biopsy frequently show metastatic tumor deposits that can establish the diagnosis. Pathologic evaluation of bone marrow is also a requirement for staging of neuroblastoma. Characteristically, neuroblastoma in bone marrow appears in clumps and pseudorosettes. The absence of pseudorosettes does not eliminate the possibility of neuroblastoma.
Laboratory studies should include measurement of urinary catecholamines and their metabolites. Either HVA or VMA, metabolites of dopa/norepinephrine and epinephrine, respectively, is elevated in >90% of patients with stage IV neuroblastoma. A ratio of VMA to HVA of >1.5 is associated with a favorable prognosis in patients with metastatic neuroblastoma. An assay for urinary VMA is the basis for screening studies of infants in Japan, Europe, and North America. Anemia secondary to bone marrow involvement with tumor can be evaluated with a complete blood cell count. Serum ferritin, lactate dehydrogenase (LDH), and other liver function indicators should be assayed routinely.
Appropriate use of imaging studies assists in staging and in planning an approach to therapy. X-ray studies demonstrate intrinsic speckled calcifications in 85% of neuroblastomas. Computed tomography (CT) of the abdomen with intravenous contrast is more sensitive than intravenous pyelography and provides more information about lymph-node or hepatic metastases as well as tumor resectability.13 Increasingly, high-quality magnetic resonance imaging (MRI) scans are replacing the routine use of CT in evaluation of suspicious thoracic or abdominal masses in children. Although MRI cannot demonstrate intratumoral calcifications, it allows better evaluation of blood vessel encasement, intraspinal extension (dumbbell tumors), diffuse hepatic replacement, and bone marrow involvement (Fig. 86.1). Each of these findings improves staging accuracy and facilitates the decision-making process regarding appropriate surgical interventions.14–17
Nuclear medicine scans are helpful in determining the extent of metastatic disease. Because neuroblastoma has a predilection for bony metastases, a radionuclide bone scan is a mandatory investigation. It is more sensitive than a skeletal survey in detecting bone metastases18 Meta-iodobenzylguanidine (MIBG) is concentrated by neurosecretory granules of both normal and neoplastic tissues of neural crest origin and can be used to image primary and metastatic sites of neuroblastoma. MIBG labeled with either 131I or 123I has a sensitivity of 85% to 90% and a specificity of almost 95% in the detection of metastatic neuroblastoma.19 Poor scintigraphic response on 123I-MIBG scans after induction chemotherapy has been shown to predict for a poor event-free survival in patients undergoing high-dose chemotherapy with stem cell rescue.20 Like other neural crest–derived neoplasms, neuroblastoma can express somatostatin receptors. The long-acting somatostatin analog octreotide labeled with 123I has been used to image neuroblastoma with a sensitivity comparable to that of 131I-MIBG.21 The expression of somatostatin receptors by neuroblastoma tissues is a favorable prognostic factor.22
The Radiology Diagnostic Oncology Group enrolled 96 children with newly diagnosed neuroblastoma in a multicenter prospective cohort study prior to surgery. CT, MRI, and bone scintigraphy were used to evaluate tumor stage. The results show that MRI is more accurate than CT for detection of stage IV disease (sensitivities 0.83 and 0.43, respectively). When combined with bone scintigraphy, both imaging tests have high accuracy for the detection of metastases. Figures 86.2 to 86.4 illustrate the value of CT and MRI in staging patients with metastatic disease. The prevalence of determinants of local disease was relatively low in this study because patients who had extensive disease at time of entry underwent delayed surgery after induction chemotherapy. Although the numbers are small, the data suggest the following: (a) in stage I tumor, abdominal extent was more likely to be staged correctly with CT than with MRI, which often overstaged tumor; (b) for stage II and III tumors, both CT and MRI were more likely to understage than overstage tumor; and (c) for stage II tumor, understaging was more likely with CT than MRI.
FIGURE 86.1. Magnetic resonance imaging scans of a 4-month-old child with a thoracic neuroblastoma. The dumbbell shape of the paraspinal mass can be appreciated on axial (A), coronal (B), and sagittal (C) images. The intraspinal component is indicated by arrows. The three views of this child’s tumor are helpful in radiation-therapy field design.
FIGURE 86.2. Neuroblastoma with nodal involvement in a 3-year-old boy. A: Computed tomography (CT) through the upper abdomen shows a large soft-tissue mass (T) arising in the right adrenal gland and extending to the midline (aorta, arrow). B: A CT scan several centimeters lower shows several small nodes (N) in the right pararenal area. C:T2-weighted axial image shows a high–signal intensity tumor (T) in the right suprarenal area. D: T2-weighted image at a lower level shows enlarged, mildly enhancing paracaval lymph nodes (N). (R, right kidney; arrow, aorta). (Courtesy of Dr. Marilyn Siegel, Mallinckrodt Institute of Radiology, St. Louis, MO.)
STAGING
The most commonly used staging system is the International Neuroblastoma Staging System (INSS). It is based on clinical, radiographic, and surgical findings.23 The INSS integrates many of the concepts of previous staging systems promoted by the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG)24,25 and unifies them into a single system. Each of these systems is summarized in Table 86.1.
PATHOLOGIC CLASSIFICATION
Neuroblastomas are derived from primitive neural crest cells arising from within sympathetic ganglia. Three types of tumors, representing different degrees of differentiation, are recognized. Ganglioneuroma consists of mature ganglion cells, Schwann cells, and nerve bundles and is benign in appearance and nature. It frequently is calcified and may represent a matured neuroblastoma.26 Cases of maturation of proven neuroblastomas to ganglioneuromas, either spontaneously or after therapy, have been reported.9 Ganglioneuroblastoma is the intermediate form between ganglioneuroma and neuroblastoma. Both mature ganglion cells and undifferentiated neuroblasts are evident.
Neuroblastoma is at the undifferentiated end of the spectrum of neural crest tumors. It is a small, round, blue cell tumor composed of dense nests of hyperchromatic cells. Homer Wright rosettes with a central fibrillary core can be present. Areas of necrosis, hemorrhage, and calcium are frequently present. Immunohistochemical stains may help distinguish neuroblastoma from other undifferentiated malignant neoplasms of childhood. Neuroblastoma characteristically stains positive for neurofilaments, neuron-specific enolase (NSE), synaptophysin, and chromogranin A and negative for muscle and leukocyte common antigens. The use of electron microscopy to demonstrate neurosecretory granules is required infrequently to establish the diagnosis.
A grading system has been proposed by Shimada et al.,27 and its significance has been confirmed by the CCG.28,29 This clinicopathologic staging system evaluates tumor specimens for stromal development (i.e., stromal-rich and stromal-poor tumors), neuroblastic differentiation, and mitosis-karyorrhexis index of neuroblastic cells. These three histologic features and the patient’s age at diagnosis divide children into favorable and unfavorable prognostic groups. The stroma-rich tumors are characterized by an extensive Schwann cell stroma. The well-differentiated stroma-rich tumors may correspond to ganglioneuroma, and the “intermixed” stroma-rich tumors may correspond to the ganglioneuroblastomas. To be reliable, the Shimada classification requires pretreatment evaluation of the entire primary tumor specimen. However, primary tumors often are not completely resectable, or the presence of widespread metastases makes thorough tumor resection inappropriate before introduction of initial systemic therapy, thereby limiting the usefulness of this system.
FIGURE 86.3. A 1-year-old child with constipation and a palpable mass, also noted to have lower leg weakness. A: Computed tomography shows a large soft-tissue mass with calcifications and necrosis filling the retroperitoneum. Tumor calcification (arrow) is noted in the spinal cord. B: Sagittal, short-tau inversion recovery image shows the large prevertebral mass displacing bowel loops superiorly. Intraspinal tumor extends from the lower thoracic level through the lumbar level. The patient underwent emergent resection of the intraspinal tumor (arrows). (Courtesy of Dr. Marilyn Siegel, Mallinckrodt Institute of Radiology, St. Louis, MO.)
FIGURE 86.4. A 6-year-old boy who presented with bone pain. Axial (A) and coronal (B) T1-weighted image of the pelvis and femurs show diffusely low–signal intensity marrow from metastases (arrows). C: Fat-saturated T2-weighted image of the pelvis. The involved marrow has increased in signal intensity and is now hyperintense to adjacent fat and soft tissue (arrows). D: Fat-saturated T2-weighted coronal image of the pelvis and femurs. Multiple high-signal foci are noted throughout the long bones (arrows). By comparison, normal marrow has a signal intensity similar to that of muscle on fat-saturated images. (Courtesy of Dr. Marilyn Siegel, Mallinckrodt Institute of Radiology, St. Louis, MO.)
TABLE 86.1 NEUROBLASTOMA STAGING SYSTEMS
PROGNOSTIC FACTORS
Patient age and stage at initial presentation remain the two most important factors that influence outcome (Table 86.2). In general >75% of infants and children <2 years old survive, as do 90% to 100% of children with INSS stages 1 and 2.30–40 The presence of tumor in regional lymph nodes is a poor prognostic factor and was recognized as such by the POG in their staging system.41 Infants <12 months old with metastatic disease confined to the liver, bone marrow (not bone), or skin (stage IV-S) have a remarkably good prognosis; <75% of these children survive with little or no treatment.8,42 Treatment should be directed at relief of the acute presenting event (often respiratory distress secondary to hepatomegaly), and the temptation to aggressively treat these patients in the absence of other bad prognostic factors should be avoided.
Patients with more-differentiated tumors (e.g., ganglioneuroma, ganglioneuroblastoma) fare better than children with poorly differentiated or undifferentiated neuroblastomas. A favorable Shimada stage is associated with 90% survival, compared with 22% with unfavorable Shimada stages. Elevated serum ferritin (>142 ng/mL), NSE (>100 ng/mL), and LDH (>1,500 IU) are all associated with advanced disease and a poor prognosis.32,43–45
MYCN (N-myc) is a proto-oncogene that resides on the short arm of chromosome 2. An increased number of MYCN gene copies is associated with an extremely poor prognosis (5% survival).46,47 MYCN amplification has been associated with the multidrug-resistance gene and may account for this tumor’s notorious resistance to therapy.48 A tumor with a DNA index of 1 (diploid or near-diploid) paradoxically gives a worse prognosis than tumors that are aneuploid.49 Hyperdiploid tumors occur more often in lower stages and are associated with better chemotherapy responsiveness. Allelic loss of the short arm of chromosome 1 represents a loss of heterozygosity of a tumor suppressor gene and is also associated with a poor prognosis independent of age and stage. It reliably identifies patients with stage I, II, or IV-S disease who have a high risk of relapse and require aggressive therapy.50
TABLE 86.2 PROGNOSTIC VARIABLES IN NEUROBLASTOMA
TABLE 86.3 NEUROBLASTOMA RISK ASSESSMENT
GENERAL MANAGEMENT
Because of the biologic heterogeneity of neuroblastoma, the following treatment recommendations should be considered as guidelines. The prognostic implications of a tumor’s biologic indices, such as MYCN amplification and DNA index, may warrant more aggressive therapy in young patients with otherwise a favorable stage (Table 86.3).
Low-Risk Disease
Low-stage, resectable tumors (INSS stage 1, 2, or 3 with negative nodes) have an excellent prognosis after complete gross surgical excision. Adjuvant chemotherapy or irradiation has not improved the outcome in children with completely resected tumors with favorable biologic features.38,51–54 Positive surgical margins or microscopic residual disease does not uniformly require more aggressive therapy. Patients with MYCN amplification or low DNA index may require adjuvant therapy and should be enrolled in clinical trials.49
Unresectable tumors that are otherwise of low stage (INSS stages 1 to 3 with negative lymph nodes) may require preoperative chemotherapy and occasionally radiation therapy to convert them into a resectable status. Second-look surgery is performed to remove a previously unresectable primary tumor and achieve a complete remission after induction chemotherapy. Complete resection can be achieved in almost two-thirds of previously unresectable stage III to IV primary tumors.55 The CCG reported that eventual complete resection of the primary tumor in advanced disease may have a favorable impact on outcome.55 The benefit to complete resection in patients with advanced disease has not been uniformly established. Patients with biologically favorable tumors may be more amenable to surgery after chemotherapy, and the apparent benefit of complete resection may be a result of patient selection.56 POG-8104 enrolled patients with INSS stage 1 (POG stage A) disease. In that trial, MYCN amplification and DNA index were not evaluated uniformly. Treatment was surgery only. Regardless of the presence of residual microscopic disease, the 2-year disease-free survival rate was 89%.25 In the CCG experience (CCG trial 3881) with stage 1 disease, the 4-year event-free and overall survival rates for children treated initially with surgery alone were 93% and 99%, respectively. For patients with stage 2 disease, the event-free and overall survival rates were 81% and 98%, respectively. In that trial, only 13% of patients with stage 2 disease received any chemotherapy or radiotherapy, despite the fact that 104 patients had INSS stage 2b disease. The authors ascribe the favorable results to improved surgical management and better staging with MIBG scanning.57
Intermediate-Risk Disease
Locally advanced and regionally metastatic tumors (INSS stage 2b to 3 with positive lymph nodes) require more intensive therapy. Infants <1 year of age should undergo complete resection of the primary tumor and receive adjuvant chemotherapy.56,58–60 In unresectable cases, chemotherapy may be administered initially, and surgery can be performed after response to systemic treatment. In older children with lymph-node metastases, adjuvant radiation therapy to the primary and regional lymph nodes has improved the disease-free and overall survival rates. A prospective, randomized trial of postoperative chemotherapy or chemotherapy plus regional irradiation demonstrated 31% disease-free survival in children treated with chemotherapy, compared with 58% in those who also received radiation therapy.61 However, the value of radiation therapy in intermediate-risk patients is not universally accepted. De Bernardi et al.62 failed to demonstrate a benefit from the addition of radiotherapy in 29 children >1 year of age with postoperative residual tumor or positive regional lymph nodes. Children in that randomized study received two cycles of peptichemio with or without radiation. Progression-free survival was 64% in the radiotherapy arm and 73% in the arm without radiotherapy.62 Coupled with the risk of late effects from even moderate radiotherapy doses, this small trial provided an argument that systematic radiation therapy, even for POG stage C patients, may not be necessary. Current COG trials reflect this bias because the use of radiation therapy is decreasing.
Patients with intraspinal extension of neuroblastoma pose a unique problem. They frequently have severe neurologic compromise resulting from spinal cord compression. Historically, these patients were treated with laminectomy and surgical debulking with or without radiation therapy and chemotherapy.63 Because the morbidity of this approach is significant, with a high rate of spinal growth deformity, a number of investigators have proceeded with treatment of these patients using primary chemotherapy.55 A prospective series of 42 patients treated with primary chemotherapy demonstrated a 92% improvement in neurologic deficits, allowing children to avoid neurosurgical decompression in >60% of cases when receiving courses of carboplatin and etoposide alternating with cyclophosphamide, vincristine, and doxorubicin.
The POG experience (POG trials 8742 and 9244) with stages 2b to 3 disease demonstrates an 85% event-free survival with completely resected tumors at diagnosis, compared to 70% with incomplete resection at diagnosis (p = .259). In both of these studies, patients underwent maximum safe tumor resection followed by five courses of induction chemotherapy. In POG-8742 they received cisplatinum and etoposide alternating with cyclophosphamide and doxorubicin. In POG-9244 they received alternating cycles of vincristine, cisplatinum, etoposide, and cyclophosphamide (OPEC) and vincristine, carboplatin, etoposide, and cyclophosphamide. After second-look surgery the same chemotherapy was given as maintenance. Radiotherapy was given to patients with viable residual tumor discovered at the time of the second-look operation. Children age 12 to 24 months at the time of radiation therapy received 24 Gy in 1.5-Gy fractions to the primary tumor site. Older children received 30 Gy in 1.5-Gy fractions. Of the 37 patients on these two protocols who survived “event free,” 11 (30%) received radiotherapy. Patients with favorable Shimada histology tumors had a 92% event-free survival, compared with 58% with unfavorable tumors (p = .009). Patients with MYCN amplification did poorly, with outcomes comparable to those for stage D patients.27
Based on CCG and POG data, patients with intermediate-risk neuroblastoma have an estimated 3-year survival of between 75% and 98%. Cyclophosphamide, doxorubicin, carboplatin, and etoposide are the four most active agents.64–66 The COG now is evaluating the role of chemotherapy dose intensity and duration for children based on tumor biology.
Surgery plays a critical role in the primary management of neuroblastoma. The goals of surgery are to establish a diagnosis; provide tissue for evaluation of prognostic biologic markers; stage the disease according to INSS criteria; and attempt to totally excise the primary, if feasible. The extent of surgery has an important impact on outcome. O’Neill et al.67 reported that 55 of 59 patients with a complete or near-complete resection were alive and free of disease 2 years after surgery, compared to only 13 of 24 cases with a subtotal resection. Just as Haase had reported, Grosfield and Baehner34 found evidence for improved outcome in stage 4 patients attaining complete resection of primary tumor at delayed second-look procedures.
High-Risk Disease
The majority of patients with neuroblastoma present with metastatic disease. With the exception of infants with favorable biologic disease confined to the skin, bone marrow, or liver, the outcome is poor. Extremely aggressive treatment regimens have been used in these patients to prolong survival and achieve cure. Intensive high-dose chemotherapy regimens appear to be superior to less intensive regimens. Active drugs in advanced neuroblastoma include cyclophosphamide, cisplatin, doxorubicin, etoposide, and teniposide.68
Many recent clinical trials have sought to intensify treatment of metastatic neuroblastoma through the use of high-dose myeloablative chemotherapy with stem cell rescue or bone marrow transplantation (BMT). The French Lyon-Marseille-Curie East group reported a 40% progression-free survival at 2 years and 20% at 5 years in 62 patients proceeding to autologous bone marrow transplant (ABMT).69 The CCG reported a 43% 2-year event-free survival in 43 children undergoing consolidation melphalan, cisplatin, teniposide, doxorubicin, and total-body irradiation (TBI) to 1,000 cGy in three fractions of 330 cGy/day. The toxic death rate was 22%.70 Australian investigators tested a less intense preparative regimen with a TBI regimen consisting of 12 Gy in six twice-daily fractions.71 Of 28 patients registered, 19 achieved complete remission after induction chemotherapy. Seventeen of these 19 patients underwent ABMT and 15 (87%) remained free of disease at 5 years from ABMT. Of the 28 patients registered, 50% have survived 5 years.
Uncertain that ABMT could be studied successfully in a cooperative group, the CCG conducted two pilot studies for children with stage 4 disease. In CCG-321, patients received induction chemotherapy consisting of cisplatin, etoposide, doxorubicin, and cyclophosphamide. Of 207 patients, 159 remained disease free during induction chemotherapy. Of these patients, 67 received myeloablative chemotherapy and ABMT, whereas 74 continued conventional chemotherapy for a total of 13 cycles. The patients receiving the ABMT had a higher event-free survival than patients continuing standard chemotherapy (40% vs. 19%, p = .019).72 Because they are not randomized trials, these studies potentially may have allowed a biased allocation of patients to one arm based on clinical concerns or prognostic risk factors. The POG failed to show a benefit to BMT in high-risk metastatic neuroblastoma (POG 8340).45
The European Neuroblastoma Study Group studied the role of consolidative ABMT with high-dose melphalan versus no further treatment following induction chemotherapy with the OPEC regimen in patients with stage 3 and 4 disease.73,74 With a median follow-up of 14.3 years for surviving children, they report an improvement in event-free survival (38% vs. 27%) and overall survival (47% and 30%) for the high-dose melphalan arm, but these differences did not reach statistical significance. The subset of patients with stage IV disease who were >1 year of age, however, did show statistically significant improvement in event-free survival (33% vs. 17%, p = .01) and overall survival (46% vs. 21%, p = .03).
The CCG conducted a randomized trial comparing continued chemotherapy with myeloablative therapy (including 10 Gy TBI in 3 daily fractions) and autologous bone marrow transplantation in children with high-risk neuroblastoma. All patients received radiation therapy to the primary site and select metastatic sites. A second randomization following cytotoxic therapy included 6 cycles of 13-cis-retinoic acid or no further therapy. Initial results demonstrated an event-free survival advantage to both bone marrow transplantation and 13-cis-retinoic acid therapy, but no overall survival advantage.75 However, after a median follow-up of more than 7 years, a statistically significant advantage to overall survival was demonstrated for the cohort treated with both myeloablative therapy and 13-cis-retinoic acid therapy.76
Berthold et al.77 in Germany reported results of a prospective, randomized trial in children with high-risk neuroblastoma comparing myeloablative therapy with melphalan, etoposide, and carboplatin and autologous stem cell rescue with maintenance chemotherapy with cyclophosphamide. When analyzed as-treated, statistically significantly improved 3-year event-free survival (53% vs. 30%) and overall survival (68% vs. 53%) were seen with myeloablative therapy.
Local control of the primary tumor in stage 4 neuroblastoma is an important element of patient management. The role of surgical resection in metastatic disease remains controversial. Many authors have reported more favorable outcome in patients undergoing complete resection.78,79 There is a strong association between chemotherapy dose intensity and surgical respectability, which reduces the significance of aggressive resection as an independent favorable factor. It can be assumed that tumors that are amenable to resection may have an inherently less aggressive biology.
In the CCG-321-P3 pilot there was a 33% rate of local relapse in patients not undergoing a complete resection at their initial surgery, irrespective of their ultimate surgical resection status, including second-look operations.80 This high local failure rate suggests that there is a role for local radiation therapy. In that pilot study, patients received radiotherapy if they had gross residual disease after second-look surgery. Although the local control in patients receiving radiotherapy was the same as in unirradiated patients, it should be noted that only patients with gross residual disease received this local treatment, suggesting that the radiotherapy (RT) was beneficial.
In a reanalysis of CCG-3891, Hass-Kogan et al.81 compared locoregional control rates in patients on the non-ABMT arm who received 10 to 20 Gy to gross residual disease after induction therapy to patients in the ABMT arm who received similar RT to residual disease but also received 10-Gy TBI in 3.33-Gy daily fractions in their conditioning regimens The patients in the ABMT arm had a lower locoregional recurrence rate (33% vs. 51%, p = .004). Although this affect may be due to the higher dose of RT delivered in this group of patients, it is not possible to separate the RT effect from that of the more intense systemic therapy also given to these patients in the ABMT arm.
Laprie et al.82 analyzed locoregional control in MYCN-amplified INSS stage 2 and 3 patients treated with different regimens over different eras. Their approach varied from conventional chemotherapy and RT only to gross residual disease after surgery in patients >1 year of age, to high-dose chemotherapy with ABMT, to local radiation therapy to all patients. They noted an improvement in event-free survival with ABMT and RT (83% vs. 25%, p = .001). Again, conclusions regarding the effect of RT independent of the intensified systemic therapy are difficult to make because this was not a randomized comparison.
Local therapy to the primary tumor and metastatic sites may be beneficial in the curative therapy of children with disseminated disease. Surgical resection of the primary tumor has been associated with improved survival and local control after aggressive systemic therapy.55,80 There is a predilection for recurrence in previous sites of disease, and it is conceivable that additional local therapy with irradiation to the primary tumor site and distant metastases may enhance tumor control and cure rates.80,83
The POG reported that patients with persistent disease at primary or metastatic sites received boost irradiation of 12 Gy prior to TBI for BMT. Only 2 of 27 patients relapsed at irradiated sites. Six of 10 first-remission patients given local radiation remained in remission, compared to only 13 of 40 who were not irradiated, despite the fact that irradiated patients had residual disease.84
Radiation therapy plays an extremely important role in the palliative management of patients with end-stage symptomatic neuroblastoma. Pain from bone or other visceral metastases often can be relieved with external-beam radiation therapy. Mass effect from a rapidly enlarging tumor can respond dramatically to radiation therapy. In a series of 10 patients treated at Duke University Medical Center, Halperin85 reported 7 complete responses to radiation therapy, either alone or in conjunction with chemotherapy. Radiation doses ranged from 4 to 24.4 Gy at a rate of 1 to 1.5 Gy/fraction. The 7 patients with complete response survived without recurrence.
Systemic radionuclide therapy with 131I-MIBG has been tested in several European and U.S. centers with early encouraging results. This radioactive agent produced objective responses in previously treated and chemoresistant stage 4 neuroblastoma.86,87 These early positive results prompted some investigators to test this agent in previously untreated metastatic neuroblastoma. DeKraker et al.88 reported that a combination of 131I-MIBG and second-look surgery produced response rates comparable to those of multidrug chemotherapy. Preliminary research on the combination of 131I-MIBG with systemic chemotherapy and/or TBI with BMT demonstrated that this is a safe treatment and worthy of more investigation.89–91
The current approach by the Children’s Oncology Group for patients with high-risk disease is to combine induction chemotherapy, surgical resection, autologous stem cell rescue, radiation therapy to the primary site and select metastatic sites, and 13-cis-retinoic acid in an attempt to improve outcome in these patients. The current protocol explores further intensification of therapy by randomizing patients to either one myeloablative transplant or two myeloablative transplants. It will also include a higher radiation total dose of 36 Gy for patients with gross residual disease at their primary sites.
FIGURE 86.5. Radiation therapy treatment field for a child with a left adrenal primary neuroblastoma and para-aortic lymph-node metastases. The beam’s–eye-view display with a digital reconstructed radiograph allows for adequate coverage of the target volume and lymph-node region with sparing of the ipsilateral kidney and liver while homogeneously irradiating the adjacent spine.
RADIATION-THERAPY TECHNIQUES: TREATMENT PLANNING AND FIELD DESIGN
Significant reductions in irradiation-associated morbidity have accompanied technological advances. The transition from orthovoltage to megavoltage x-rays has decreased the risk of severe growth-related skeletal defects.92 CT-assisted simulation and three-dimensional radiation-therapy treatment planning have the potential to decrease the volume of normal tissues irradiated and thereby decrease the incidence of late effects (Fig. 86.5). As in Wilms’ tumor, the radiation oncologist must be aware of the increased risk of spinal deformity or other skeletal anomalies if symmetric irradiation of the bone is not administered. The clinician needs to balance the treatment of disease and normal tissues to maximize tumor coverage while not sacrificing the growing tissues.
Radiation therapy portals to a primary tumor site should treat the gross residual tumor remaining after chemotherapy with at least a 2-cm margin from the tumor to the block edge. This margin usually ensures adequate dosimetric coverage of the residual tumor, taking into account treatment-related positional uncertainties and beam penumbra. Children who are not sedated may require more margin if they tend to shift or move on the treatment table. Regional lymph-node sites should be covered if nodes were radiographically or pathologically involved at any time during the disease course. The POG study that demonstrated an advantage to radiation therapy for POG stage C disease included extended-field radiation therapy to adjacent lymph-node sites (i.e., elective mediastinal irradiation for abdominal primary tumors).61 It is not clear that this extended-field treatment contributed to the beneficial effect of radiation therapy, and current POG trials do not include it. Halperin93 reviewed the patterns of failure in 13 children with stage C neuroblastoma treated with systemic therapy and radiation therapy directed to the primary tumor and without “prophylactic” irradiation of contiguous lymph-node regions. Of the 7 patients who failed, 2 of them developed a recurrence in contiguous lymph-node regions. In both these circumstances these regional failures were accompanied by local or distant failure. Considering the morbidity associated with the additional radiation volume and its impact on the tolerance to subsequent chemotherapy, he recommended against this prophylactic regional irradiation.
CT or MRI scans should be used to define the full extent of disease when a radiation therapy portal is designed. In many instances, parallel opposed anterior and posterior portals may suffice for tumor coverage. They have the added advantage of allowing homogeneous irradiation of the spine in paraspinal tumors.
Radiation therapy of metastatic sites should include generous margins. Bony metastases often are more extensive than a plain radiograph may suggest. Orbital metastases may require treatment of the entire orbit. Hepatic metastases do not require whole-liver irradiation, but adequate margins must be used to account for respiratory motion during treatment. The patient’s life expectancy should influence the selection of radiation-therapy portals, field shaping, and dose fractionation. Children who have end-stage disease with tumors that are resistant to most chemotherapy drugs should be treated with wide fields and a rapid fractionation schedule. Complex field design and prolonged fractionation schedules may prevent the terminal child from spending quality time off therapy. The exception is infants with stage 4S disease. These children frequently have a very good prognosis, and sparing of normal tissues is an important goal.
Low-dose TBI has been used with variable success in the curative management of children with metastatic neuroblastoma.94,95 More important has been the use of TBI as part of the preparative regimen for patients undergoing BMT for high-risk metastatic disease. It is not clear if TBI is essential in the preoperative program for a transplant. Patterns of failure after BMT are predominately in sites of prior disease, including the original primary tumor and previously documented metastatic sites.80,83 These data suggest that involved-field boost irradiation, before or after BMT with TBI, may be beneficial.
The appropriate radiation dose is debatable. Laboratory data suggest that neuroblastoma is very radiosensitive and that neuroblasts exhibit very little repair capacity between fractions.96 This makes hyperfractionated radiation therapy an attractive option because comparable tumoricidal doses can be achieved with minimization of the risk of late effects.97,98 However, despite irradiation doses that approach normal-tissue tolerance in the young, local recurrences after radiation therapy still occur. The irradiation dose required to control gross disease may be age dependent.29,39,99 In infants <1 year of age, a dose of 12 Gy appears sufficient for durable local control.29,99 Tumors in children aged 12 to 48 months may require doses of at least 25 Gy. Children >4 years of age frequently develop local failures even with doses of > 25 Gy. Local control of the primary tumor site in patients with high-risk disease may be improved with the use of local radiation to the primary site and regional lymph nodes. Kushner et al.52 updated the experience from Memorial Sloan-Kettering Cancer Center, reporting that 21 Gy of hyperfractionated radiation therapy resulted in 90% primary-site local control at 5 years. Radiation was delivered after all chemotherapy with a minimum interval of 4 hours between fractions. No TBI was administered in this group of patients. If patients had a gross total resection, the local control was 100%, whereas in seven patients with gross disease, three had recurrence.52,100 In Kushner et al.’s series, 92% of metastatic sites were controlled with 21 Gy of hyperfractionated radiation therapy at 36 months.
Haas-Kogan101 described the results of intraoperative radiation therapy (IORT) in patients with high-risk disease. A single fraction of 7 to 16 Gy (median 10 Gy) to the primary tumor bed was associated with a local control rate of 100% in patients who had gross total resection, whereas IORT was unable to control any patients with gross residual disease.
Children treated palliatively for symptomatic metastatic disease should receive adequate irradiation doses for durable tumor control if they have a reasonable expectation of long survival. Total dose and fractionation regimens similar to those used for curative therapy should be considered. Low-dose, short-fractionation schedules are appropriate if the child is not expected to live beyond 6 to 12 months. In these instances, minimizing a child’s visits to the radiation-therapy facility while rapidly relieving symptoms is a worthwhile goal. If the likelihood of long survival is small, 5 to 20 Gy in one to five daily fractions can allow rapid palliation.
RESULTS OF THERAPY
Low-Risk Disease
Survival rates after surgery alone of 85% to 90% or better can be expected.25,51,54,57,102 Additional therapy usually is not indicated unless unfavorable biologic features are present.
Intermediate-Risk Disease
Children with large, initially unresectable tumors often respond to primary chemotherapy with combinations of drugs, including cyclophosphamide, vincristine, cisplatin, etoposide, doxorubicin, or teniposide. Children with unresponsive, unresectable gross residual disease may require external-beam irradiation. Frequently, these children can undergo resection of the tumor at a second-look operation55 and achieve a survival rate of 60% to 90%.54,102
The presence of lymph-node metastases, even with a localized primary tumor, negatively affects prognosis. These children have a 50% to 75% survival rate even with aggressive systemic therapy and adjuvant radiation therapy.61,102 Infants with lymph node–positive disease have a more favorable outcome, with a 3-year disease-free survival rate of 93% after treatment with cyclophosphamide and doxorubicin and complete resection without irradiation.59
High-Risk Disease
Children >1 year of age with metastatic neuroblastoma continue to have a poor prognosis, with expected 3- or 4-year survival rates of <10% to 30%. The addition of cisplatin and teniposide to the chemotherapy armamentarium improved the expected 4-year survival rate from 7% to 28% in a series of trials conducted from 1962 to 1988 at St. Jude Children’s Research Hospital.58 The CCG reported that ABMT can improve outcome in selected patients with metastatic neuroblastoma. With this aggressive therapy, the 3-year event-free survival was 34%. The addition of cis-retinoic acid was associated with a 47% event-free survival.75 The COG is investigating even more intensive systemic therapy with tandem stem cell transplant.
Infants with metastatic disease have a uniquely favorable outcome. In stage 4S, survival rates can be as high as 75% to 90%.103,104 In these patients, the goal of therapy should be limited to the relief of acute presenting symptoms. Local-field, fractionated low-dose irradiation (<12 Gy), minimal chemotherapy, or supportive care may be sufficient to achieve high survival rates. Infants with metastases to other sites (brain, bone, or lung) or who have tumors with poor biologic features (DNA index of 1, MYCNamplification) should be managed with more aggressive regimens.49,105 Halperin85 reported 7 complete responses to hepatic radiation in 10 infants with symptomatic liver metastases. All 7 of these children survived.
TABLE 86.4 WASHINGTON UNIVERSITY NEUROBLASTOMA STUDY OF LONG-TERM SEQUELAE RELATED TO RADIATION THERAPY
SEQUELAE OF TREATMENT
Early Complications
Acute side effects of radiation therapy depend on tumor site and fields of treatment. The short-term effects are those that can be expected for any patient receiving radiation therapy. Acute effects, especially skin reactions and mucositis, may be enhanced if concurrent chemotherapy or a hyperfractionated irradiation schedule is used.
Late Effects
Long-term effects depend on the site irradiated and the total dose of both radiation and chemotherapy agents used. Age at the time of treatment may influence the risk and severity of skeletal anomalies,106 which may include spinal deformities such as kyphosis, scoliosis, or limb shortening. Generally, younger children are more prone to late radiation injury than older children. Fortunately, in neuroblastoma, the youngest children require radiation therapy infrequently or at lower total doses. Table 86.4 lists the late sequelae associated with radiation therapy in the management of neuroblastoma at Washington University.107 Chemotherapy may increase the risk of irradiation sequelae, and the expected tolerance may be reduced.108
Neve et al.109 reported a high rate of pulmonary function impairment in children receiving TBI as part of their conditioning regimen for ABMT. The impairment was most severe in younger children or patients requiring more chemotherapy. TBI was fractionated: a total of 12 Gy was given in six fractions over 3 days, with a dose rate of 50 cGy/minute with lung shielding at 10 Gy. TBI also has been associated with poor growth in survivors of neuroblastoma treated with ABMT. Hovi et al.110 described a series of 31 children, 15 of whom were treated with high-dose chemotherapy and no TBI and 16 of whom received TBI of 10 to 12 Gy in five or six fractions over 3 days. After 10 years of follow-up, the height standard deviation score of the TBI group was –2.0 compared to –0.7 to –0.9 for the nonirradiated group. This loss of height may have been related to growth-hormone deficiency. The majority of patients in both groups responded to growth hormone deficiency with a mean increase in their height standard deviation score of 0.8 at 3 years.
REFERENCES
1. Woods WG, Tuchman M, Bernstein ML, et al. Screening for neuroblastoma in North America: 2-year results from the Quebec Project. Am J Pediatr Hematol Oncol 1992;14(4):312–319.
2. Schilling FH, Berthold F, Erttmann R, et al. Population-based and controlled study to evaluate neuroblastoma screening at one year of age in Germany: interim results. Med Pediatr Oncol 2000;35(6):701–704.
3. Schilling FH, Spix C, Berthold F, et al. Neuroblastoma screening at one year of age. N Engl J Med 2002;346(14):1047–1053.
4. Woods WG, Gao RN, Shuster JJ, et al. Screening of infants and mortality due to neuroblastoma. N Engl J Med 2002;346(14):1041–1046.
5. Yamamoto K, Ohta S, Ito E, et al. Marginal decrease in mortality and marked increase in incidence as a result of neuroblastoma screening at 6 months of age: cohort study in seven prefectures in Japan. J Clin Oncol2002;20(5):1209–1214.
6. Murphy SB, Cohn SL, Craft AW, et al. Do children benefit from mass screening for neuroblastoma: consensus statement from the American Cancer Society Workshop on Neuroblastoma Screening. Lancet 1991;337(8737):344–346.
7. Yamamoto K, Hayaski Y, Hanada R, et al. Mass screening and age-specific incidence of neuroblastoma in Suitama Prefecture Japan. J Clin Oncol 1995;13(8):2033–2038.
8. Evans AE, Chatten J, D’Angio GJ, et al. A review of 17-IV-S neuroblastoma patients at the Children’s Hospital of Philadelphia. Cancer 1980;45(4):833–839.
9. Everson EC, Cole WH. Spontaneous regression of cancer. Philadelphia: WB Saunders, 1966:88–163.
10. Beckwith JB, Perrin EV. In situ neuroblastomas: a contribution to the natural history of neural crest tumors. Am J Pathol 1963;43:1089–1104.
11. Bray PF, Ziter FA, Lahey ME, et al. The coincidence of neuroblastoma and acute cerebellar encephalopathy. J Pediatr 1969;75(6):983–990.
12. Pranzatelli MR The neurobiology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol 1992;19(1):1–47.
13. Boechat MI, Ortega J, Hoffman AD, et al. Computed tomography in stage III neuroblastoma. AJR Am J Roentgenol 1985;145:1283–1287.
14. Couanet D, Geoffray A, Hartmann O, et al. Bone marrow metastases in children’s neuroblastoma studies by magnetic resonance imaging. Prog Clin Biol Res 1988;271:547–555.
15. Fletcher BD, Kopiwoda SY, Strandjord SE, et al. Abdominal neuroblastoma: magnetic resonance imaging and tissue characterization. Radiology 1985;155(3):699–703.
16. Petrus LV, Hall TR, Boechat MI, et al. The pediatric patient with suspected adrenal neoplasm: which radiological test to use? Med Pediatr Oncol 1992;20(1):53–57.
17. Siegel M, Jamroz GA, Glazer HS, et al. MR imaging of intraspinal extension of neuroblastoma. J Comput Assist Tomogr 1986;10(4):593–595.
18. Turba E, Fagioli G, Mancini AF, et al. Evaluation of stage 4 neuroblastoma patients by means of MIBG and 99mTc-MDP scintigraphy. J Nucl Biol Med 1993;37(3):107–114.
19. Shapiro B. Imaging of catecholamine-secreting tumors: uses of MIBG in diagnosis and treatment. Ballieres Clin Endocrinol Metab 1993;7(2):491–507.
20. Katzenstein HM, Cohn SL, Shore RM, et al. Scintigraphic response by 123I-metaiodobenzylguanidine scan correlates with event-free survival in high-risk neuroblastoma. J Clin Oncol 2004;22(19):3909–3915.
21. O’dorisio MS, Hauger M, Cecalupo AJ. Somatostatin receptors in neuroblastoma: diagnosis and therapeutic implications. Semin Oncol 1994;21(5, Suppl 13):33–37.
22. Moertel CL, Reubi JC, Scheithaur BS. Expression of somatostatin receptors in childhood neuroblastoma. Am J Clin Pathol 1994;102(6):752–756.
23. Brodeur GM, Seeger RC, Barrett A, et al. International criteria for diagnosis staging and response to treatment in patients with neuroblastoma. J Clin Oncol 1988;6(12):1874–1881.
24. Evans AE, D’Angio GJ, Randolph J. A proposed staging for children with neuroblastoma. Children’s cancer study group A. Cancer 1971;27(2):374–378.
25. Nitschke R, Smith EI, Shochat S, et al. Localized neuroblastoma treated by surgery: a Pediatric Oncology Group study. J Clin Oncol 1988;6(8):1271–1279.
26. Willis RA. The pathology of tumors in children. Springfield IL: Charles C Thomas, 1962:7–17.
27. Shimada H, Chatten J, Newton WA, et al. Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst1984;73(7):405–416.
28. Chatten J, Shimada H, Sather HN, et al. Prognostic value of histopathology in advanced neuroblastoma: a report from the Children’s Cancer Study Group. Hum Pathol 1988;19(10):1187–1198.
29. Jacobson GM, Sause WT, O’Brien RT. Dose response analysis of pediatric neuroblastoma to megavoltage radiation. Am J Clin Oncol 1984;7(6):693–697.
30. Carlsen NL, Christensen IJ, Schroeder H, et al. Prognostic factors in neuroblastoma treated in Denmark from 1943 to 1980: a statistical estimate of prognosis based on 253 cases. Cancer 1986;58(12):2726–2735.
31. Coldman AJ, Fryer CJH, Elwood JM, et al. Neuroblastoma: influence of age at diagnosis stage tumor site and sex on prognosis. Cancer 1980;46(8):1896–1901.
32. Evans AE, D’Angio GJ, Propert K, et al. Prognostic factors in neuroblastoma. Cancer 1987;59(11):1853–1859.
33. Evans AE, D’Angio GJ, Sather HN, et al. A comparison of four staging systems for localized and regional neuroblastoma: a report from the Children’s Cancer Study Group. J Clin Oncol 1990;8(4):678–688.
34. Grosfeld JL, Baehner RL. Neuroblastoma: an analysis of 160 cases. World J Surg 1980;4(1):29–37.
35. Halperin EC, Cox EB. Radiation therapy in the management of neuroblastoma: the Duke University Medical Center experience 1967–1984. Int J Radiat Oncol Biol Phys 1986;12(10):1829–1837.
36. Hayes FA, Green AA. Neuroblastoma. Pediatr Ann 1983;12(5):366–367.
37. Hayes FA, Thompson EI, Huizdala E, et al. Chemotherapy as an alternative to laminectomy and radiation in the management of epidural tumor. J Pediatr 1984;104(2):221–224.
38. Ninane J, Wese FX. Treatment of localized neuroblastoma. Am J Pediatr Hematol Oncol 1986;8(3):248–252.
39. Rosen EM, Cassady JR, Frantz CN, et al. Neuroblastoma: the Joint Center for Radiation Therapy/Dana Farber Cancer Institute/Children’s Hospital experience. J Clin Oncol 1984;2(7):719–732.
40. Simone JV. The treatment of neuroblastoma. J Clin Oncol 1984;2(7):717–718.
41. Hayes FA, Green AA, Hustu HO, et al. Surgicopathologic staging of neuroblastoma: prognostic significance of regional lymph node metastases. J Pediatr 1983;102:59.
42. Evans AE, Baum E, Chard R. Do infants with stage IV-S neuroblastoma need treatment? Arch Dis Child 1981;56(4):271–274.
43. Berthold F, Trechow R, Utsch S, et al. Prognostic factors in metastatic neuroblastoma: a multivariate analysis of 182 cases. Am J Pediatr Hematol Oncol 1992;14:207–215.
44. Brodeur G, Castleberry R. Neuroblastoma. In: Pizzo P, Poplack D, eds. Principles and practice of pediatric oncology. Philadelphia: Lippincott Williams & Wilkins, 1993:739–767.
45. Shuster J, McWilliams N, Castleberry R, et al. Serum lactate dehydrogenase in childhood neuroblastoma: a Pediatric Oncology Group recursive partitioning study. Am J Clin Oncol 1992;15(4):295–303.
46. Brodeur GM, Seeger RC, Schwab M, et al. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 1984;224(4653):1121–1124.
47. Seeger RC, Brodeur GM, Sather H, et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 1985;313(18):1111–1116.
48. Norris MD, Bordow SB, Marshall GM, et al. Expression of the gene for multidrug-resistance-associated protein and outcome in patients with neuroblastoma. N Engl J Med 1996;334(4):231–238.
49. Look A, Hayes FA, Shuster J, et al. Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group Study. J Clin Oncol 1991;9(4):581–591.
50. Caron H, van Sluis P, De Kraker J, et al. Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med 1996;334(4):225–230.
51. Evans AE, Brand W, de Lorimier A, et al. Results in children with local and regional neuroblastoma managed with and without vincristine cyclophosphamide and imidazole carboxamide: a report from the Children’s Cancer Study Group. Am J Clin Oncol1984;6:3.
52. Kushner BH, Cheung N-K, LaQuaglia MP, et al. International neuroblastoma staging system stage 1 neuroblastoma: a prospective study and literature review. J Clin Oncol 1996;14(7):2174–2180.
53. Matthay KK, Sather HN, Seeger RC, et al. Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy. J Clin Oncol 1989;7(2):236–244.
54. Nitschke R, Smith EI, Altshuler G, et al. Postoperative treatment of nonmetastatic visible residual neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 1991;9(7):1181–1188.
55. Haase GM, O’Leary MC, Ramsay NKC, et al. Aggressive surgery combined with intensive chemotherapy improves survival in poor-risk neuroblastoma. J Pediatr Surg 1991;26(9):11119–1123.
56. Shorter NA, Davidoff AM, Evans AE, et al. The role of surgery in the management of stage IV neuroblastoma: a single institution study. Med Pediatr Oncol 1995;24(5):287–291.
57. Perez CA, Matthay KK, Atkinson JB, et al. Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a Children’s Cancer Group study. J Clin Oncol 2000;18(1):18–26.
58. Bowman LC, Hancock ML, Santana VM, et al. Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St. Jude Children’s Research Hospital experience 1962–1988. J Clin Oncol1991;9:1599–1608.
59. Castleberry RP, Shuster JJ, Altshuler G, et al. Infants with neuroblastoma and regional lymph node metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group study. J Clin Oncol1992;10(8):1299–1304.
60. Guglielmi M, DeBernardi B, Rizzo A, et al. Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course? J Clin Oncol 1996;14(5):1537–1544.
61. Castleberry RP, Kun LE, Shuster JJ, et al. Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma. J Clin Oncol 1991;9(5):789–795.
62. de Bernardi B, Rogers D, Carli M, et al. Localized neuroblastoma: surgical and pathologic staging. Cancer 1987;60:1066–1072.
63. Plantaz D, Rubie H, Michon J, et al. The treatment of neuroblastoma with intraspinal extension with chemotherapy followed by surgical removal of residual disease. Cancer 1996;78(2):311–319.
64. Castleberry RP, Cantor AB, Green AA, et al. Phase II investigational window using carboplatin iproplatin ifosfamide and epirubicin in children with untreated disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 1994;12(8):1616–1620.
65. Ettinger LJ, Gaynon PS, Krailo MD, et al. A phase II study of carboplatin in children with recurrent or progressive solid tumors: a report from the Childrens Cancer Group. Cancer 1994;73(4):1297–1301.
66. Philip T, Gentet JC, Carrie C, et al. Phase II studies of combinations of drugs with high dose carboplatin in neuroblastoma (800 mg/m2 to 1 g 250/m2): a report from the LMCE group. Prog Clin Biol Res 1988;271:573–582.
67. O’Neill JA, Littman P, Blitzer P, et al. The role of surgery in localized neuroblastoma. J Pediatr Surg 1985;20(6):708–712.
68. Cheung NV, Heller G. Chemotherapy dose intensity correlates strongly with response median survival and median progression-free survival in metastatic neuroblastoma (Review). J Clin Oncol 1991;9(6):1050–1058.
69. Philip T, Zucker JM, Bernard JL, et al. Improved survival at 2 and 5 years in the LMCE1 unselected group of 72 children with stage IV neuroblastoma older than 1 year of age at diagnosis: is cure possible in a small subgroup? J Clin Oncol 1991;9(6):1037–1044.
70. Seeger RC, Villablanca JG, Matthay KK, et al. Intensive chemoradiotherapy and autologous bone marrow transplantation for poor prognosis neuroblastoma. Prog Clin Biol Res 1991;366:527–533.
71. McCowage GB, Vowels MR, Shaw PJ, et al. Autologous bone marrow transplantation for advanced neuroblastoma using teniposide doxorubicin melphalan cisplatin and total body irradiation. J Clin Oncol 1995;13(11):2789–2795.
72. Stram DO, Matthay KK, O’Leary M, et al. Consolidation chemoradiotherapy and autologous bone marrow transplantation versus continued chemotherapy for metastatic neuroblastoma: a report of two concurrent Children’s Cancer Group studies. J Clin Oncol 1996;14(9):2417–2426.
73. Pinkerton CR. ENSG 1-randomized study of high-dose melphalan in neuroblastoma. Bone Marrow Transplant 1991;7(Suppl 3):112–113.
74. Pritchard J, Cotterill SJ, Germond SM, et al. High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer2005;44(4):348–357.
75. Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy radiotherapy autologous bone marrow transplantation and 13-cis-retinoic acid. Children’s Cancer Group. New Engl J Med1999;341(16):1165–1173.
76. Matthay KK, et al. Long-term results for children with high-risk neuroblastoma treated on randomized trial of myeloblative therapy followed by 13-cis-retinoic acid: a Children’s Oncology Group Study. J Clin Oncol2009;27(7):1007–1013.
77. Berthold F, Boos J, Burdach S, et al. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol2005;6(9):649–658.
78. Cecchetto G, Luzzatto C, Carli M, et al. The role of surgery in non-localized neuroblastoma. Analysis of 59 cases. Tumori 1983;69(4):327–329.
79. La Quaglia MP, Kushner BH, Heller G, et al. Stage 4 neuroblastoma diagnosed at more than 1 year of age: gross total resection and clinical outcome. J Pediatr Surg 1994;29(8):1162–1165.
80. Matthay KK, Atkinson JB, Stram DO, et al. Patterns of relapse after autologous purged bone marrow transplantation for neuroblastoma: a Children’s Cancer Group pilot study. J Clin Oncol 1993;11(11):2226–2233.
81. Haas-Kogan DA, Swift PS, Selch M, et al. Impact of radiotherapy for high-risk neuroblastoma: a Children’s Cancer Group study. Int J Radiat Oncol Biol Phys 2003;56(1):28–39.
82. Laprie A, Michon J, Hartmann O, et al. High-dose chemotherapy followed by locoregional irradiation improves the outcome of patients with international neuroblastoma staging system stage II and III neuroblastoma with MYCN amplification. Cancer2004;101(5):1081–1089.
83. Sibley GS, Mundt AJ, Goldman S, et al. Patterns of failure following total body irradiation and bone marrow transplantation with or without a radiotherapy boost for advanced neuroblastoma. Int J Radiat Oncol Biol Phys1995;32(4):1127–1135.
84. Graham-Pole J, Casper J, Elfenbein G, et al. High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 1991;9:152.
85. Halperin EC. Hepatic metastasis from neuroblastoma. South Med J 1987;80(11):1370–1373.
86. Hutchinson RJ, Sisson JC, Shapiro B, et al. 131-I-metaiodobenzylguanidine treatment in patients with refractory advanced neuroblastoma. Am J Clin Oncol 1992;15(3):226–232.
87. Lashford LS, Lewis IJ, Fielding SL, et al. Phase I/II study of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: a United Kingdom Children’s Cancer Study Group investigation. J Clin Oncol1992;10(12):1889–1896.
88. DeKraker J, Hoefnagel CA, Caron H, et al. First line targeted radiotherapy: a new concept in the treatment of advanced stage neuroblastoma. Eur J Cancer 1995;31A(4):600–602.
89. Gaze MN, Wheldon TE, O’Donoghue JA, et al. Multi-modality megatherapy with [131I]meta-iodobenzylguanidine high dose melphalan and total body irradiation with bone marrow rescue: feasibility study of a new strategy for advanced neuroblastoma. Eur J Cancer 1995;31A(2):252–256.
90. Mastrangelo R, Tornesello A, Riccardi R, et al. A new approach in the treatment of stage IV neuroblastoma using a combination of [131I]meta-iodobenzylguanidine (MIBG) and cisplatin. Eur J Cancer 1995;31A(4):606–611.
91. Yanik GA, Levine JE, Matthay KK, et al. Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma. J Clin Oncol2002;20(8):2142–2149.
92. Thomas PR, Griffith KD, Fineberg BB, et al. Late effects of treatment for Wilms’ Tumor. Int J Radiat Oncol Biol Phys 1983;9(5):651–657.
93. Halperin EC Long-term results of therapy for stage C neuroblastoma. J Surg Oncol Suppl 1996;63(3):172–178.
94. D’Angio GJ, Evans A. Cyclic low-dose total body irradiation for metastatic neuroblastoma. Int J Radiat Oncol Biol Phys 1983;9:1961.
95. Kun LE, Casper JT, Kline RW, et al. Fractionated total body irradiation for metastatic neuroblastoma. Int J Radiat Oncol Biol Phys 1981;7(11):1599–1602.
96. Wheldon TE, Wilson L, Livingstone A, et al. Radiation studies on multicellular tumor spheroids derived from human neuroblastoma: absence of sparing effect of dose fractionation. Eur J Cancer Clin Oncol 1986;22(5):563–566.
97. Eifel PJ. Decreased bone growth arrest in weanling rats with multiple radiation fractions per day. Int J Radiat Oncol Biol Phys 1988;15(1):141–145.
98. Eifel PJ, Sampson CM, Tucker SL. Radiation fractionation sensitivity of epiphyseal cartilage in a weanling rat model. Int J Radiat Oncol Biol Phys 1990;19(3):661–664.
99. Michalski JM, Ratheesan K, Grigsby PW. Neuroblastoma: treatment and patient factors influencing local tumor control by radiotherapy. In: Proceedings of the American Radium Society 87th Annual Meeting, Paris, 1995.
100. Wolden SL, Gollamudi SV, Kushner BH, et al. Local control with multimodality therapy for stage 4 neuroblastoma. Int J Radiat Oncol Biol Phys 2000;46(4):969–974.
101. Haas-Kogan DA. Int J Radiat Oncol Biol Phys 2000;47(4):985–992.
102. Haase GM, Atkinson JB, Stram DO, et al. Surgical management and outcome of locoregional neuroblastoma: comparison of the Children’s Cancer Group and the International Staging Systems. J Pediatr Surg 1995;30(2):289–294.
103. Nickerson HJ, Nesbit ME, Grosfeld JL, et al. Comparison of stage IV and IV-S neuroblastoma in the first year of life. Med Pediatr Oncol 1985;13(5):261–268.
104. Strother D, Shuster JJ, McWilliams N, et al. Results of Pediatric Oncology Group 8104 for infants with stages D and DS neuroblastoma. J Pediatr Hematol Oncol 1995;17(3):254–259.
105. Paul SR, Tarbell NJ, Korf B, et al. Stage IV neuroblastoma in infants: long-term survival. Cancer 1991;67(6):1493–1497.
106. Wallace WH, Shalet SM. Chemotherapy with actinomycin D influences the growth of the spine following abdominal irradiation. Med Pediatr Oncol 1992;20(2):177.
107. Thomas PRM, Lee JY, Fineberg BB, et al. An analysis of neuroblastoma at a single institution. Cancer 1984;53(10):2079–2082.
108. Wallace WHB, Shalet SM, Morris-Jones PH, et al. Effect of abdominal irradiation on growth in boys treated for a Wilms’ tumor. Med Pediatr Oncol 1990;18(6):441–446.
109. Neve V, Foot AB, Michon J, et al. Longitudinal clinical and functional pulmonary follow-up after megatherapy fractionated total body irradiation and autologous bone marrow transplantation for metastatic neuroblastoma. Med Pediatr Oncol1999;32(3):170–176.
110. Hovi L, Saarinen-Pihkala UM, Vettenranta K, et al. Growth in children with poor-risk neuroblastoma after regimens with or without total body irradiation in preparation for autologous bone marrow transplantation. Bone Marrow Transplant1999;24(10):1131–1136.